Tag: exercise

Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Gulf War Illness affects 25–30% of American veterans deployed to the 1990–91 Persian Gulf War and is characterized by cognitive post-exertional malaise following physical effort. Gulf War Illness remains controversial since cognitive post-exertional malaise is also present in the more common Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. An objective dissociation between neural substrates for cognitive post-exertional malaise in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome would represent a biological basis for diagnostically distinguishing these two illnesses.

Here, we used functional magnetic resonance imaging to measure neural activity in healthy controls and patients with Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome during an N-back working memory task both before and after exercise. Whole brain activation during working memory (2-Back > 0-Back) was equal between groups prior to exercise. Exercise had no effect on neural activity in healthy controls yet caused deactivation within dorsal midbrain and cerebellar vermis in Gulf War Illness relative to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients.

Further, exercise caused increased activation among Myalgic Encephalomyelitis/Chronic Fatigue Syndrome patients within the dorsal midbrain, left operculo-insular cortex (Rolandic operculum) and right middle insula. These regions-of-interest underlie threat assessment, pain, interoception, negative emotion and vigilant attention. As they only emerge post-exercise, these regional differences likely represent neural substrates of cognitive post-exertional malaise useful for developing distinct diagnostic criteria for Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Source: Stuart D Washington, Rakib U Rayhan, Richard Garner, Destie Provenzano, Kristina Zajur, Florencia Martinez Addiego, John W VanMeter, James N Baraniuk, Exercise alters brain activation in Gulf War Illness and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, Brain Communications, Volume 2, Issue 2, 2020, fcaa070, https://doi.org/10.1093/braincomms/fcaa070 https://academic.oup.com/braincomms/article/2/2/fcaa070/5885074 (Full text)

Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI)

Abstract:

Background: Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) are two debilitating disorders that share similar symptoms of chronic pain, fatigue, and exertional exhaustion after exercise. Many physicians continue to believe that both are psychosomatic disorders and to date no underlying etiology has been discovered. As such, uncovering objective biomarkers is important to lend credibility to criteria for diagnosis and to help differentiate the two disorders.

Methods: We assessed cognitive differences in 80 subjects with GWI and 38 with CFS by comparing corresponding fMRI scans during 2-back working memory tasks before and after exercise to model brain activation during normal activity and after exertional exhaustion, respectively. Voxels were grouped by the count of total activity into the Automated Anatomical Labeling (AAL) atlas and used in an “ensemble” series of machine learning algorithms to assess if a multi-regional pattern of differences in the fMRI scans could be detected.

Results: A K-Nearest Neighbor (70%/81%), Linear Support Vector Machine (SVM) (70%/77%), Decision Tree (82%/82%), Random Forest (77%/78%), AdaBoost (69%/81%), Naïve Bayes (74%/78%), Quadratic Discriminant Analysis (QDA) (73%/75%), Logistic Regression model (82%/82%), and Neural Net (76%/77%) were able to differentiate CFS from GWI before and after exercise with an average of 75% accuracy in predictions across all models before exercise and 79% after exercise. An iterative feature selection and removal process based on Recursive Feature Elimination (RFE) and Random Forest importance selected 30 regions before exercise and 33 regions after exercise that differentiated CFS from GWI across all models, and produced the ultimate best accuracies of 82% before exercise and 82% after exercise by Logistic Regression or Decision Tree by a single model, and 100% before and after exercise when selected by any six or more models. Differential activation on both days included the right anterior insula, left putamen, and bilateral orbital frontal, ventrolateral prefrontal cortex, superior, inferior, and precuneus (medial) parietal, and lateral temporal regions. Day 2 had the cerebellum, left supplementary motor area and bilateral pre- and post-central gyri. Changes between days included the right Rolandic operculum switching to the left on Day 2, and the bilateral midcingulum switching to the left anterior cingulum.

Conclusion: We concluded that CFS and GWI are significantly differentiable using a pattern of fMRI activity based on an ensemble machine learning model.

Source: Provenzano D, Washington SD, Rao YJ, Loew M, Baraniuk J. Machine Learning Detects Pattern of Differences in Functional Magnetic Resonance Imaging (fMRI) Data between Chronic Fatigue Syndrome (CFS) and Gulf War Illness (GWI). Brain Sci. 2020;10(7):E456. Published 2020 Jul 17. doi:10.3390/brainsci10070456 https://www.mdpi.com/2076-3425/10/7/456 (Full text)

Post-exertional Symptoms Distinguish Myalgic encephalomyelitis/chronic Fatigue Syndrome Subjects From Healthy Controls

Abstract:

Background: Post-exertional malaise (PEM) is an exacerbation of symptoms that leads to a reduction in functionality. Recognition of PEM is important for the diagnosis and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

Objective: Symptoms following cardiopulmonary exercise testing were compared between ME/CFS patients and healthy controls.

Methods: Open-ended questionnaires were provided to subjects following two maximal exercise tests, 24 hours apart. Subjects evaluated how they felt at five time points. Responses were classified into 19 symptom categories.

Results: ME/CFS subjects (n = 49) reported an average of 14±7 symptoms compared to 4±3 by controls (n = 10). During the seven days afterwards, ME/CFS subjects reported 4±3 symptoms. None were reported by controls. Fatigue, cognitive dysfunction, and sleep problems were reported with the greatest frequency. ME/CFS patients reported more symptom categories at higher frequencies than controls. The largest differences were observed in cognitive dysfunction, decrease in function, and positive feelings.

Conclusions: A standardized exertional stimulus produced prolonged, diverse symptoms in ME/CFS subjects. This provides clues to the underlying pathophysiology of ME/CFS, leading to improved diagnosis and treatment.

Source: Mateo LJ, Chu L, Stevens S, et al. Post-exertional symptoms distinguish myalgic encephalomyelitis/chronic fatigue syndrome subjects from healthy controls [published online ahead of print, 2020 Jun 16]. Work. 2020;10.3233/WOR-203168. doi:10.3233/WOR-203168 https://pubmed.ncbi.nlm.nih.gov/32568143/

Physical Activity Measures in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Correlations Between Peak Oxygen Consumption, the Physical Functioning Scale of the SF-36 Questionnaire, and the Number of Steps From an Activity Meter

Abstract:

Background: Most studies to assess effort intolerance in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) have used questionnaires. Few studies have compared questionnaires with objective measures like an actometer or an exercise test. This study compared three measures of physical activity in ME/CFS patients: the physical functioning scale (PFS) of the SF-36, the number of steps/day (Steps) using an actometer, and the %peak VO2 of a cardiopulmonary stress test.

Methods: Female ME/CFS patients were selected from a clinical database if the three types of measurements were available, and the interval between measurements was ≤ 3 months. Data from the three measures were compared by linear regression.

Results: In 99 female patients the three different measures were linearly, significantly, and positively correlated (PFS vs Steps, PFS vs %peak VO2 and Steps vs %peak VO2: all P < 0.001). Subgroup analysis showed that the relations between the three measures were not different in patients with versus without fibromyalgia and with versus without a maximal exercise effort (RER ≥ 1.1). In 20 patients re-evaluated for symptom worsening, the mean of all three measures was significantly lower (P < 0.0001), strengthening the observation of the relations between them. Despite the close correlation, we observed a large variation between the three measures in individual patients.

Conclusions: Given the large variation in ME/CFS patients, the use of only one type of measurement is inadequate. Integrating the three modalities may be useful for patient care by detecting overt discrepancies in activity and may inform studies that compare methods of improving exercise capacity.

Source: van Campen CMC, Rowe PC, Verheugt FWA, Visser FC. Physical activity measures in patients with myalgic encephalomyelitis/chronic fatigue syndrome: correlations between peak oxygen consumption, the physical functioning scale of the SF-36 questionnaire, and the number of steps from an activity meter. J Transl Med. 2020;18(1):228. Published 2020 Jun 8. doi:10.1186/s12967-020-02397-7 https://pubmed.ncbi.nlm.nih.gov/32513266/

Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome

Abstract:

BACKGROUND: In myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), altered membrane excitability often occurs in exercising muscles demonstrating muscle dysfunction regardless of any psychiatric disorder. Increased oxidative stress is also present in many ME/CFS patients and could affect the membrane excitability of resting muscles.

METHODS: Seventy-two patients were examined at rest, during an incremental cycling exercise and during a 10-min post-exercise recovery period. All patients had at least four criteria leading to a diagnosis of ME/CFS. To explore muscle membrane excitability, M-waves were recorded during exercise (rectus femoris (RF) muscle) and at rest (flexor digitorum longus (FDL) muscle). Two plasma markers of oxidative stress (thiobarbituric acid reactive substance (TBARS) and oxidation-reduction potential (ORP)) were measured. Plasma potassium (K+) concentration was also measured at rest and at the end of exercise to explore K+ outflow.

RESULTS: Thirty-nine patients had marked M-wave alterations in both the RF and FDL muscles during and after exercise while the resting values of plasma TBARS and ORP were increased and exercise-induced K+ outflow was decreased. In contrast, 33 other patients with a diagnosis of ME/CFS had no M-wave alterations and had lower baseline levels of TBARS and ORP. M-wave changes were inversely proportional to TBARS and ORP levels.

CONCLUSIONS: Resting muscles of ME/CFS patients have altered muscle membrane excitability. However, our data reveal heterogeneity in some major biomarkers in ME/CFS patients. Measurement of ORP may help to improve the diagnosis of ME/CFS.

Trial registration Ethics Committee “Ouest II” of Angers (May 17, 2019) RCB ID: number 2019-A00611-56.

Source: Jammes Y, Adjriou N, Kipson N, Criado C, Charpin C, Rebaudet S, Stavris C, Guieu R, Fenouillet E, Retornaz F. Altered muscle membrane potential and redox status differentiates two subgroups of patients with chronic fatigue syndrome. J Transl Med. 2020 Apr 19;18(1):173. doi: 10.1186/s12967-020-02341-9. https://www.ncbi.nlm.nih.gov/pubmed/32306967

Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender-specific changes in the microRNA expression profiling in ME/CFS

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystem illness characterized by medically unexplained debilitating fatigue with suggested altered immunological state. Our study aimed to explore peripheral blood mononuclear cells (PBMCs) for microRNAs (miRNAs) expression in ME/CFS subjects under an exercise challenge. The findings highlight the immune response and inflammation links to differential miRNA expression in ME/CFS.

The present study is particularly important in being the first to uncover the differences that exist in miRNA expression patterns in males and females with ME/CFS in response to exercise. This provides new evidence for the understanding of differential miRNA expression patterns and post-exertional malaise in ME/CFS.

We also report miRNA expression pattern differences associating with the nutritional status in individuals with ME/CFS, highlighting the effect of subjects’ metabolic state on molecular changes to be considered in clinical research within the NINDS/CDC ME/CFS Common Data Elements.

The identification of gender-based miRNAs importantly provides new insights into gender-specific ME/CFS susceptibility and demands exploration of sex-suited ME/CFS therapeutics.

© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Source: Cheema AK, Sarria L, Bekheit M, Collado F, Almenar-Pérez E, Martín-Martínez E, Alegre J, Castro-Marrero J, Fletcher MA, Klimas NG, Oltra E, Nathanson L. Unravelling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): Gender-specific changes in the microRNA expression profiling in ME/CFS. J Cell Mol Med. 2020 Apr 14. doi: 10.1111/jcmm.15260. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/32291908

Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention

Abstract:

One quarter of veterans returning from the 1990–1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise.

One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task (“see a letter, push a button”) performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI).

The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia–anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks.

These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.

Source: Clarke T, Jamieson JD, Malone P, Rayhan RU, Washington S, VanMeter JW, et al. (2019) Connectivity differences between Gulf War Illness (GWI) phenotypes during a test of attention. PLoS ONE 14(12): e0226481. https://doi.org/10.1371/journal.pone.0226481 https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226481 (Full text)

A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control

Abstract:

Chronic Fatigue Syndrome (CFS) is a debilitating condition estimated to impact at least 1 million individuals in the United States, however there persists controversy about its existence. Machine learning algorithms have become a powerful methodology for evaluating multi-regional areas of fMRI activation that can classify disease phenotype from sedentary control. Uncovering objective biomarkers such as an fMRI pattern is important for lending credibility to diagnosis of CFS.

fMRI scans were evaluated for 69 patients (38 CFS and 31 Control) taken before (Day 1) and after (Day 2) a submaximal exercise test while undergoing the n-back memory paradigm. A predictive model was created by grouping fMRI voxels into the Automated Anatomical Labeling (AAL) atlas, splitting the data into a training and testing dataset, and feeding these inputs into a logistic regression to evaluate differences between CFS and control. Model results were cross-validated 10 times to ensure accuracy. Model results were able to differentiate CFS from sedentary controls at a 80% accuracy on Day 1 and 76% accuracy on Day 2 (Table 3).

Recursive features selection identified 29 ROI’s that significantly distinguished CFS from control on Day 1 and 28 ROI’s on Day 2 with 10 regions of overlap shared with Day 1 (Figure 3). These 10 shared regions included the putamen, inferior frontal gyrus, orbital (F3O), supramarginal gyrus (SMG), temporal pole; superior temporal gyrus (T1P) and caudate ROIs. This study was able to uncover a pattern of activated neurological regions that differentiated CFS from Control.

This pattern provides a first step toward developing fMRI as a diagnostic biomarker and suggests this methodology could be emulated for other disorders. We concluded that a logistic regression model performed on fMRI data significantly differentiated CFS from Control.

Source: Provenzano D, Washington SD, Baraniuk JN. A Machine Learning Approach to the Differentiation of Functional Magnetic Resonance Imaging Data of Chronic Fatigue Syndrome (CFS) From a Sedentary Control. Front Comput Neurosci. 2020 Jan 29;14:2. doi: 10.3389/fncom.2020.00002. eCollection 2020. https://www.ncbi.nlm.nih.gov/pubmed/32063839

Maximal handgrip strength can predict maximal physical performance in patients with chronic fatigue

Abstract:

BACKGROUND: Maximal handgrip strength is used to predict exercise performance in healthy older subjects and in patients with chronic obstructive pulmonary disease, breast cancer or cirrhosis. Our objective was to evaluate the ability of maximal handgrip strength to predict maximal exercise performance in patients with chronic fatigue.

METHODS: Sixty-six patients with myalgic encephalomyelitis/chronic fatigue syndrome and 32 patients with chronic fatigue but no diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome were included. The maximal physical performance was measured on a cycle ergometer to measure the peak oxygen uptake and the maximal work rate. We searched for linear regressions between maximal handgrip strength and maximal performances.

FINDINGS: No significant differences in slopes and ordinates of regression lines were noted between patients with or without a diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome, allowing to pool the data. Maximal handgrip strength was significantly and positively correlated with peak oxygen uptake and maximal work rate in all patients with chronic fatigue.

INTERPRETATION: We conclude that handgrip strength can predict maximal exercise performance in patients with chronic fatigue.

Source: Jammes Y, Stavris C, Charpin C, Rebaudet S, Lagrange G, Retornaz F. Maximal handgrip strength can predict maximal physical performance in patients with chronic fatigue. Clin Biomech (Bristol, Avon). 2020 Jan 9;73:162-165. doi: 10.1016/j.clinbiomech.2020.01.003. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31986462

Exercise therapy for chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) or myalgic encephalomyelitis (ME) is a serious disorder characterised by persistent postexertional fatigue and substantial symptoms related to cognitive, immune and autonomous dysfunction. There is no specific diagnostic test, therefore diagnostic criteria are used to diagnose CFS. The prevalence of CFS varies by type of diagnostic criteria used. Existing treatment strategies primarily aim to relieve symptoms and improve function. One treatment option is exercise therapy.

OBJECTIVES: The objective of this review was to determine the effects of exercise therapy for adults with CFS compared with any other intervention or control on fatigue, adverse outcomes, pain, physical functioning, quality of life, mood disorders, sleep, self-perceived changes in overall health, health service resources use and dropout.

SEARCH METHODS: We searched the Cochrane Common Mental Disorders Group controlled trials register, CENTRAL, and SPORTDiscus up to May 2014, using a comprehensive list of free-text terms for CFS and exercise. We located unpublished and ongoing studies through the World Health Organization International Clinical Trials Registry Platform up to May 2014. We screened reference lists of retrieved articles and contacted experts in the field for additional studies.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) about adults with a primary diagnosis of CFS, from all diagnostic criteria, who were able to participate in exercise therapy.

DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, ‘Risk of bias’ assessments and data extraction. We combined continuous measures of outcomes using mean differences (MDs) or standardised mean differences (SMDs). To facilitate interpretation of SMDs, we re-expressed SMD estimates as MDs on more common measurement scales. We combined dichotomous outcomes using risk ratios (RRs). We assessed the certainty of evidence using GRADE.

MAIN RESULTS: We included eight RCTs with data from 1518 participants.Exercise therapy lasted from 12 weeks to 26 weeks. The studies measured effect at the end of the treatment and at long-term follow-up, after 50 weeks or 72 weeks.

Seven studies used aerobic exercise therapies such as walking, swimming, cycling or dancing, provided at mixed levels in terms of intensity of the aerobic exercise from very low to quite rigorous, and one study used anaerobic exercise. Control groups consisted of passive control, including treatment as usual, relaxation or flexibility (eight studies); cognitive behavioural therapy (CBT) (two studies); cognitive therapy (one study); supportive listening (one study); pacing (one study); pharmacological treatment (one study) and combination treatment (one study).Most studies had a low risk of selection bias. All had a high risk of performance and detection bias.

Exercise therapy compared with ‘passive’ control. Exercise therapy probably reduces fatigue at end of treatment (SMD -0.66, 95% CI -1.01 to -0.31; 7 studies, 840 participants; moderate-certainty evidence; re-expressed MD -3.4, 95% CI -5.3 to -1.6; scale 0 to 33). We are uncertain if fatigue is reduced in the long term because the certainty of the evidence is very low (SMD -0.62, 95 % CI -1.32 to 0.07; 4 studies, 670 participants; re-expressed MD -3.2, 95% CI -6.9 to 0.4; scale 0 to 33).

We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.99, 95% CI 0.14 to 6.97; 1 study, 319 participants).Exercise therapy may moderately improve physical functioning at end of treatment, but the long-term effect is uncertain because the certainty of the evidence is very low. Exercise therapy may also slightly improve sleep at end of treatment and at long term. The effect of exercise therapy on pain, quality of life and depression is uncertain because evidence is missing or of very low certainty.

Exercise therapy compared with CBT. Exercise therapy may make little or no difference to fatigue at end of treatment (MD 0.20, 95% CI -1.49 to 1.89; 1 study, 298 participants; low-certainty evidence), or at long-term follow-up (SMD 0.07, 95% CI -0.13 to 0.28; 2 studies, 351 participants; moderate-certainty evidence).

We are uncertain about the risk of serious adverse reactions because the certainty of the evidence is very low (RR 0.67, 95% CI 0.11 to 3.96; 1 study, 321 participants).The available evidence suggests that there may be little or no difference between exercise therapy and CBT in physical functioning or sleep (low-certainty evidence) and probably little or no difference in the effect on depression (moderate-certainty evidence). We are uncertain if exercise therapy compared to CBT improves quality of life or reduces pain because the evidence is of very low certainty.

Exercise therapy compared with adaptive pacing. Exercise therapy may slightly reduce fatigue at end of treatment (MD -2.00, 95% CI -3.57 to -0.43; scale 0 to 33; 1 study, 305 participants; low-certainty evidence) and at long-term follow-up (MD -2.50, 95% CI -4.16 to -0.84; scale 0 to 33; 1 study, 307 participants; low-certainty evidence).

We are uncertain about the risk of serious adverse reactions (RR 0.99, 95% CI 0.14 to 6.97; 1 study, 319 participants; very low-certainty evidence).The available evidence suggests that exercise therapy may slightly improve physical functioning, depression and sleep compared to adaptive pacing (low-certainty evidence). No studies reported quality of life or pain.Exercise therapy compared with antidepressants. We are uncertain if exercise therapy, alone or in combination with antidepressants, reduces fatigue and depression more than antidepressant alone, as the certainty of the evidence is very low. The one included study did not report on adverse reactions, pain, physical functioning, quality of life, sleep or long-term results.

AUTHORS’ CONCLUSIONS: Exercise therapy probably has a positive effect on fatigue in adults with CFS compared to usual care or passive therapies. The evidence regarding adverse effects is uncertain. Due to limited evidence it is difficult to draw conclusions about the comparative effectiveness of CBT, adaptive pacing or other interventions. All studies were conducted with outpatients diagnosed with 1994 criteria of the Centers for Disease Control and Prevention or the Oxford criteria, or both. Patients diagnosed using other criteria may experience different effects.

Source: Larun L, Brurberg KG, Odgaard-Jensen J, Price JR. Exercise therapy for chronic fatigue syndrome. Cochrane Database Syst Rev. 2019 Oct 2;10:CD003200. doi: 10.1002/14651858.CD003200.pub8. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/31577366